Researchers have a new lead on why HIV has been so hard to cure, and a potential new strategy for driving the virus from one of its last major hiding places in the body.

Patients can live for decades with HIV infection as long as they take antiviral drugs that stop the virus from making copies of itself, known as replicating.

But the virus is never gone. It lies dormant in a part of the immune system called resting memory T cells, making it basically invisible to the body’s defenses.

However, “as soon as patients stop taking the drugs, the virus comes out of this latent state and starts replicating again,” said Johns Hopkins University HIV researcher Robert Siliciano. “That’s why you can’t cure anybody with the drugs.”

Doctors have hoped if they can decloak the virus while the patient is taking antivirals, the body’s own defenses would spot the infected cells and destroy them, and the drugs could keep the virus from spreading.

But so far that hasn’t worked.

One reason, Siliciano and colleagues write in the journal"Nature"the virus that comes out of hiding looks different than the one that caused the infection.

Master of disguise

HIV is a master of disguise, like a spy on the run. Secret agents can change their coat and color their hair, then they might duck into a closet until the coast is clear.

Likewise, HIV is constantly mutating to evade the immune system. That's where the drugs come in. If the virus fools the germ hunters, called killer T cells, the antiviral drugs can still kill it. Except for the altered virus that has gone into hiding in the memory T cells.

The new study found that when the virus comes out of hiding, nearly all of it is mutated -- still wearing a disguise that most of the killer T cells don’t recognize.

Most, but not all, and that's the key.

“Other cells see different parts of virus that have not mutated. Those cells can still be effective,” Siliciano said. There are fewer of them, and “they have to be stimulated in right way, but once they’re stimulated, they can recognize and eliminate those infected cells.”

Spot the shoes

Like training spy hunters to spot the secret agent’s shoes, Siliciano showed this smaller group of killer T cells a piece of the virus that had not changed. That stimulated them to find and kill most of the infected memory T cells.

It’s good news, but it’s too soon to celebrate, Siliciano cautions.

“Whether it would kill enough of them to allow a patient to go off treatment and not have the virus come back, we don’t know,” he said.

National Institute of Allergy and Infectious Disease Director Anthony Fauci agrees. While the research shows a promising route to boost the body’s ability to tamp down the infection, he said, “I think it’s far too premature to be thinking that this a major step towards a cure, because getting a cure for HIV is going to be a very complicated, difficult thing that might not even be attainable,” he said.

Still, according to virologist David Margolis at the University of North Carolina at Chapel Hill, who was not involved in the research, it’s a brighter assessment than a study Siliciano published just a few years ago.

“It painted a darker picture, like it would be very hard or impossible to get rid of latently infected cells,” Margolis said. According to the new research, he added, “it does look pretty straightforward to think of ways that we could re-target the immune response to clear that virus.”

Siliciano said researchers may be able to develop a vaccine that would stimulate the killer T cells. Patients on antivirals would get the vaccine and then a drug to wake the sleeping virus.

Half the battle

But everyone agrees there are major hurdles to clear before scientists can talk about a cure for HIV.

“Half the battle is killing the cells once you turn the virus back on,” Siliciano said. “Probably the harder part is actually just turning the virus back on. We still are looking for ways to do that.”

Diagnosing HIV earlier might also be a factor.

The study found that when patients started treatment within a few weeks of infection, almost none of the virus that went into hiding had mutated into an unrecognizable form.

For those patients, he said, “it may be easier to eliminate infected cells once you reverse latency.”

“It’s clear for a number of reasons that the earlier patients starts treatment, the better,” he noted.

He spent eight years in molecular biology and infectious disease research before deciding that writing about science was more fun than doing it. He graduated from the University of North Carolina at Chapel Hill with a master’s degree in journalism in 2002.